WORLD HEALTH ORGANIZATION DEPARTMENT OF NUTRITION FOR HEALTH AND DEVELOPMENT
EVIDENCE AND PROGRAMME GUIDANCE UNIT
Intermittent iron and folic acid supplementation
for prevention of anaemia in menstruating women and adolescent girls
This submission was prepared by Dr Juan Pablo Pena-Rosas with technical input from Dr Luz
Maria De-Regil, Dr Lisa Rogers, and Harinder Chahal.
EML Section 10.1 - Antianaemia Medicines
Page 1 of 23
Table of Contents Acronyms and abbreviations .......................................................................................................2
Executive summary .....................................................................................................................3
I. Background and rationale for the application........................................................................5
II. Background on iron-deficiency anaemia ...........................................................................5
1. Public health relevance .....................................................................................................5
2. Current public health interventions ...................................................................................6
3. Proposed public health intervention ..................................................................................6
III. Methods ...........................................................................................................................7
1. Methods for assessment of dosing, efficacy and safety......................................................7
2. Methods for the assessment of costs .................................................................................7
3. Methods for the assessment of current availability amongst Member States ......................7
4. Assessment of the evidence ..............................................................................................7
IV. Regulatory information on iron supplements ....................................................................7
V. Analysis of costs...............................................................................................................8
VII. Current NEML availability evaluation ..............................................................................9
VIII. Evidence on dosing, efficacy and safety of intermittent iron and folic acid
supplementation ........................................................................................................................ 11
1. Quality of the evidence ................................................................................................... 12
2. Summary of the evidence ............................................................................................... 12
IX. WHO guidelines on intermittent iron and folic acid supplementation .............................. 13
X. Summary and recommendations ..................................................................................... 15
XI. References ...................................................................................................................... 16
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Acronyms and abbreviations CI 95% Confidence interval
BNF British National Formulary
EC Expert committee
EML Essential Medicines List (for adults)
EMLc Essential Medicines List (for children)
FDA Food and Drug Administration
GRADE Grading of Recommendations Assessment, Development and Evaluation
LMICs Low and middle-income countries
MD Mean difference
MSH Management Sciences for Health
MHRA Medicines and Healthcare Products Regulatory Agency
RR Relative risk
SRA Stringent Regulatory Authority
TGA Therapeutic Goods Administration
UK United Kingdom
UNICEF United Nations’ Children Fund
USD United States dollar
WHO World Health Organization
Page 3 of 23
Executive summary This application presents a comprehensive review of the evidence for the effective use of
intermittent supplementation (that is one, two or three times a week on non-consecutive days)
with 60 mg elemental iron plus 2.8 mg of folic acid in menstruating women and adolescent girls
as a public health intervention in areas where anaemia prevalence is 20% or higher and there are
no interventions to control anaemia in place..
Evidence summarized in a Cochrane review shows that intermittent supplementation with iron
(either alone or in combination with other nutrients) is significantly more effective in reducing
anaemia among menstruating women compared to receiving no supplementation or placebo
(average relative risk (RR) 0.73, 95% confidence interval (CI) 0.56 to 0.95). Evidence from 13
studies (2599 participants) showed a significant increase in haemoglobin concentration (mean
difference (MD) 4.58 g/l, 95% CI 2.56 to 6.59) with supplementation. Additionally, 6 studies
(980 participants) showed that supplementation significantly increases ferritin concentrations
(MD 8.32 μg/l, 95% CI 4.97 to 11.66) compared to receiving no intervention or placebo.
Benefits were observed with intermittent supplementation with iron when given either alone or
in combination with folic acid or other micronutrients. However, compared to women receiving
daily iron supplements, women receiving iron supplements intermittently were more likely to
have anaemia (RR 1.26, 95% CI 1.04 to 1.51) and have lower serum/plasma ferritin
concentrations (MD -11.32 μg/l, 95% CI -22.61 to -0.02, although they had similar haemoglobin
concentrations (MD -0.15 g/l, 95% CI -2.20 to 1.91).
The review found evidence that intermittent supplementation with iron (with or without folic
acid) in menstruating women is effective in decreasing the risk of anaemia, and increasing
haemoglobin and ferritin concentrations. Positive effects of intermittent supplementation were
seen in patients receiving iron once or twice per week. Furthermore, the haematological
responses were evaluated with supplements containing more or less than 60 mg of elemental iron
per week for a duration of 3 months or less or more than 3 months.
The most common side-effects of iron supplementation include nausea, constipation, dark stools,
and metallic taste. The current evidence suggests there is no significant difference in adverse
side-effects between once weekly intermittent iron supplementation versus no intervention or
placebo (RR 1.98, 95% CI 0.31 to 12.72) and between once weekly intermittent iron
supplementation versus daily iron supplementation (RR 0.36, 95% CI 0.10 to 1.31).
The recommendations for changes to the EML Section 10.1 - Antianaemia Medicines, are as
follow:
1. Add 60 mg elemental iron in a ferrous form plus folic acid 2.8 mg tablet/capsule
formulation for the prevention of anaemia in menstruating women and adolescent
girls. The frequency and duration of the intermittent supplementation is as follow:
a. One tablet per week
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b. Three months of supplementation followed by 3 months of no
supplementation after which the provision of supplements should restart.
i. If feasible, intermittent supplements could be given throughout the school
or calendar year
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I. Background and rationale for the application Daily supplementation with iron and folic acid for a period of 3 months has been the
standard approach for the prevention and treatment of iron deficiency anaemia among
women of reproductive age. Despite its proven efficacy, there has been limited success
with the daily regimen public health programmes, which is thought to be primarily due
to low coverage rates, insufficient tablet distribution and, low adherence because of the
side-effects (e.g. constipation, dark stools or metallic taste). Intermittent use of oral iron
supplements (i.e. once, twice or three times a week on non-consecutive days) has been
used as an effective alternative to daily iron supplementation to prevent anaemia among
menstruating women.
The 18th
EC requested a review of evidence to determine the appropriate dosing of iron
and folic acid combination in menstruating women to prevent anaemia (1). A Cochrane
review was commissioned to gather evidence in 2011, followed by the development of
WHO guidelines on Intermittent iron and folic acid supplementation in menstruating
women. (2, 3). This EML application presents evidence summarized in the Cochrane
review and proposes recommendations for the EMLc.
II. Background on iron-deficiency anaemia Iron-deficiency anaemia occurs as a result of decreased haemoglobin concentration in the
blood and decreased iron concentrations, leading to iron deficiency (4). The causes of
anaemia are several, including parasitic infections, inflammatory disorders, disorders of
haemoglobin structure, or vitamin and mineral deficiencies, including iron and folate (4).
It is estimated that at least half the burden of anaemia is due to iron deficiency and can be
induced by sustained negative iron balance due to inadequate dietary intake, absorption
or utilization of iron or chronic loss of iron due to bleeding (4). Women, during
reproductive age, are at higher risk of developing iron deficiency due to menstruation.
With prolonged iron deficiency, the haemoglobin concentration starts to decrease,
resulting in iron deficiency anaemia (3). Haemoglobin is responsible for carrying oxygen
from the lungs to the tissue; therefore, during anaemia, the blood has a decreased capacity
to carry oxygen through the blood leading to a deficit of oxygen in the body of the
affected individual, leading to a series of functional problems (3). Iron deficiency
anaemia is diagnosed by measuring haemoglobin concentration, along with serum ferritin
and transferrin concentrations (5-7). A decrease in these values by predefined laboratory
measures that differ by age and sex indicate iron-deficiency anaemia.
1. Public health relevance The world-wide prevalence of anaemia in non-pregnant women is estimated at 30.2%.
Anaemia impairs resistance to infection and reduces physical capacity and work
performance among all age groups (4). In addition, women with anaemia who become
pregnant are at higher risk of negative maternal and neonatal outcomes (4).
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2. Current public health interventions The standard approach used for prevention of anaemia in menstruating women where
prevalence of anaemia is higher than 40%is daily supplementation with iron and folic
acid for a period of 3 months (8). Although this method of supplementation is effective,
the success with daily supplementation has been limited (8). This limited success is
attributed to low coverage rates, insufficient supplement distribution, and low adherence
due to the side-effects of iron supplements, such nausea, constipation, dark stools and
metallic taste (4). In 2009 a temporary statement on Weekly iron and folic acid
supplementation was released by WHO and updated in 2011 according to the procedures
stipulated in the WHO handbook for guideline development.
3. Proposed public health intervention In order to minimize side-effects associated with iron supplementation and increase
adherence, intermittent use of oral iron and folic acid supplements is recommended as an
effective to prevent anaemia among menstruating women and adolescent girls in areas
where no other interventions are in place or where daily iron supplementation has proven
not to be effective. The rationale for this intervention is that intestinal cells turn over
every 5–6 days and have limited iron absorptive capacity (3). Thus intermittent provision
of iron would expose only the new epithelial cells to this nutrient, which may improve the
efficiency of absorption (3). Intermittent supplementation may also reduce oxidative
stress and the frequency of other side-effects associated with daily iron supplementation
such as nausea and constipation as well as minimize blockage of absorption of other
minerals due to the high iron levels in the gut lumen and in the intestinal epithelium (3).
Furthermore, experience has shown that intermittent regimens may also be more
acceptable to women and increase compliance with supplementation (9).
Additionally, the use of this regimen can result in the improvement in women’s folate
status prior to pregnancy, which may help prevent some congenital anomalies,
specifically neural tube defects (3). Child growth, development and risk of chronic
disease later in life depend, in part, on maternal iron nutrition during pregnancy. The
prevention of both anaemia and iron deficiency in menstruating women and girls prior to
pregnancy and the assurance of desirable iron reserves prior to pregnancy is an important
public health goal that requires multi-pronged, integrated and flexible approaches (9).
Iron and folate deficiency may occur concurrently in menstruating women and girls,
particularly during or after pregnancy. Because of the essential role for folate in
erythropoiesis, combined iron and folic acid supplementation may be required to ensure
an optimal haematological response in menstruating women and girls. Because of the role
of folate in preventing neural tube defects (10), women should have a folate level that is
likely to protect against congenital anomalies before entering pregnancy, especially
where pregnancies are not planned. The neural tube closes by day 28 of pregnancy, a
period when pregnancy may not have been detected. Folic acid supplementation after the
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first month of pregnancy will not prevent neural tube defects, but will contribute to other
aspects of maternal and fetal health.
III. Methods
1. Methods for assessment of dosing, efficacy and safety
A Cochrane review was commissioned to determine if any evidence existed on
intermittent iron and folic acid supplementation in menstruating women, and if so, what
are the safe and effective doses of the interventions (2). The reviewers assessed
randomized and quasi-randomized trials with either individual or cluster randomization in
which the participants were non-pregnant women beyond menarche and prior to
menopause (2). The intervention assessed was intermittent iron supplementation (with or
without folic acid and other micronutrients) compared with a placebo, no intervention or
daily supplementation (2). More than 10 international databases were searched and an
equal number of international agencies were contacted for unpublished reports.
2. Methods for the assessment of costs For tablets containing 60 mg elemental iron and 2.8 mg folic acid, the 2011 edition of the
International Drug Price Indicator Guide and the UNICEF Supply Catalogue website
were searched ((16,17).
3. Methods for the assessment of current availability amongst Member
States A survey of National Lists of Essential Medicine (NEMLs) of 20 low and middle income
countries was undertaken to determine availability of iron supplement formulations and
folic acid supplements (18).
4. Assessment of the evidence Strength and quality of evidence was assessed using the Grading of Recommendations
Assessment, Development and Evaluation (GRADE) methodology (19).
IV. Regulatory information on iron supplements Both iron and folic acid supplements are currently on the EML for adults; furthermore,
iron supplements are not reviewed for safety or efficacy and are not approved for sale as
medications by the Stringent Regulatory Authorities (SRAs) in United States (Food and
Drug Administration, FDA), Australia (Therapeutic Goods Administration, TGA) and the
United Kingdom (Medicines and Healthcare products Regulatory Agency, MHRA) (20-
22). Rather supplements are registered as food supplements and are held to good
manufacturing practices for purities only (22). Therefore, no additional specific analysis
of regulatory status of iron or folic acid supplements was warranted. However,
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manufacturers of supplements must be registered entities and certified to adhere to good
manufacturing practices (23).
V. Analysis of costs VI. Currently there are no available iron and folic acid supplements in the market for this
intervention with the recommended composition. No Fe 60+FA 2.8 mg manufacturer
found. WPRO has been actively searching for a qualified manufacturer, however, the
company making the product does not have all certificates yet.
The most recent International Drug Price Indicator Guide (16) and the UNICEF Supply
Catalogue (17) were used to compile the cost of iron and folic acid supplements. A
combination formulation of ferrous salt 60 mg elemental iron plus 2.8 mg folic acid was
not found. Single nutrient formulations and the combination of only 60 mg elemental
iron plus 0.4 mg folic acid tablets were found.
Table 1 - Cost of tablets containing 60 mg elemental iron plus 2.8 mg folic acid
Source Compound Form Cost per tablet or
mL (USD)*
MSH 2011 Ferrous Salt 60-65 mg tab/cap 0.0024 (median)
UNICEF Ferrous salt 60 mg tab 0.00311
MSH 2011 Folic Acid 5mg tab 0.0023 (median)
UNICEF Folic acid 5 mg tabs 0.00429
MSH 2011 Folic Acid 1 mg tab 0.0277 (median)
MSH 2011 Ferrous salt + folic acid 60 mg elemental iron
plus 0.4 mg folic acid
(tab)
0.0029 (median)
UNICEF
Ferrous fumarate +
folic acid
60 mg elemental iron
plus 0.4 mg folic acid
(tab)
0.00507
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VII. Current NEML availability evaluation While there are several projects in countries targeting women and adolescent girls
through weekly iron and folic acid supplementation, and it is now a policy for
implementation in India, there are not suppliers with the formulation recommended.
NEMLs of 20 LMICs were reviewed to determine current availability of iron and folic
acid supplements containing 60 mg elemental iron plus 2.8 mg folic acid combined, 60
mg of elemental iron tablets (either alone or in combination with folic acid), and folic
acid supplements containing 1 mg or 5 mg per tablet/capsule (16).
The table below shows that the majority of countries’ NEMLs contain iron and folic acid
supplements. However, most NEMLs did not specify the elemental iron content of the
formulations.
None of the NEMLs surveyed contained a combination of 60 mg elemental iron with 2.8
mg folic acid. This is as expected since this formulation is not currently on the EML or
EMLc, and most LMICs use the model WHO EML/EMLc to build their respective
national formularies (18).
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# country 60 mg
elemental
iron
folic acid
1 mg
folic acid 5
mg
60 mg elemental iron
plus folic acid 2.8 mg
Notes (…)
1 Angola … No Yes No Ferrous sulfate 200 mg found, unknown elemental iron content
2 Bangladesh … … … No Ferrous salt liquid and tablet found, unknown elemental iron content. Folic Acid
tablet found, unknown strength.
3 Bhutan Yes No Yes No Ferrous sulfate 60 mg tablet in combination with 0.4 mg folic acid
4 Central
African
Republic
… … … No Ferrous salt liquid and tablet found, unknown elemental iron content. Folic Acid
tablet found, unknown strength.
5 China … … … No Ferrous salt tablet found, unknown elemental iron content. Folic Acid tablet
found, unknown strength
6 Democratic
Republic of
Congo
… No Yes No Ferrous sulfate liquid and 200 mg + 5 mg folic acid tablet found, unknown
elemental iron content
7 Ecuador … … … No Ferrous salt liquid and tablet found, unknown elemental iron content. Folic acid –
the NEML list tablet strength range 0.5 – 5 mg.
8 Fiji … No Yes No Ferrous salt liquid and tablet found, unknown elemental iron content.
9 Ghana Yes No Yes No Ferrous salt liquid found, unknown elemental iron content.
10 India No No No No Ferrous salt liquid and tablet (20mg elemental iron) in combination with 100mcg
folic acid found.
11 Honduras … Yes Yes No Ferrous salt tablet (65 mg elemental iron) found
12 Lesotho … No Yes No Ferrous salt liquid and tablet found, unknown elemental iron content.
13 Malaysia … No Yes No Ferrous salt tablet found, unknown elemental iron content.
14 Namibia … No Yes No Ferrous salt tablet (65 mg elemental iron) found; Ferrous salt liquid found,
unknown elemental iron content.
15 Oman … Yes Yes No Ferrous salt tablet (45 – 70 mg elemental iron) found; Ferrous salt liquid (15
mg/0.6 mL elemental iron) found.
16 Pakistan Yes Yes Yes No
17 Rwanda Yes Yes Yes No
18 Senegal … No Yes No Ferrous salt liquid and tablet found, unknown elemental iron content.
19 Thailand … No Yes No Ferrous salt liquid and tablet found, unknown elemental iron content.
20 Vanuatu … No Yes No Ferrous salt liquid and tablet found, unknown elemental iron content.
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VIII. Evidence on dosing, efficacy and safety of intermittent iron and
folic acid supplementation Based on the Cochrane review, pertinent outcomes of efficacy are presented here.
Summary of Findings (GRADE) tables are presented in Appendix A to provide details on
the evidence from which the recommendations were made (2).
The review included 21 trials with 10,258 participants from 15 countries in Latin
America, Africa and Asia from 1997 to 2010. In 11 of the 21 trials, the duration of
supplementation was less than 3 months and in the others the maximum duration was 6
months (2).
Iron alone was provided in nine trials, while eight trials assessed efficacy of iron plus
folic acid supplementation and two studies used iron plus multiple micronutrient
supplements (2). All except two trials used iron sulfate as the iron salt for
supplementation (2).
The Cochrane group undertook 6 comparisons of evidence:
1. Comparison 1: Intermittent iron supplementation versus placebo or no
intervention
2. Comparison 2: Intermittent iron supplementation versus daily iron
supplementation
For each comparison listed, a summary of information on three outcomes (anaemia,
haemoglobin and ferritin) is provided in Appendix B. For each outcome, the following
factors were considered: 1) the overall effect size of the intervention, 2) effect size with
supplementation of 60 mg (or less) of elemental iron per week, 3) effect size with iron
supplementation alone, and 4) effect size with supplementation of a combination of iron
and folic acid. There are other several studies on folic acid absorption and retention in
the body since 1975 and while there is plenty of evidence that 80%-100% of a folic acid
dose may be absorbed, it seems clear that much less is retained and contributes to
improved status. The fraction of a dose that is retained within the tissues seems to depend
on the dose and ultimately on renal handling and the threshold where excess folic acid
spills into the urine. The evidence points out that 2.8 mg of folic acid weekly in New
Zealand is efficacious in elevating erythrocyte folate concentrations above 905 µmol/L
and in reducing homocysteine levels (11). Similar results have been observed with a 5 mg
weekly dose in Mexico (12,13). In intervention trials where supplements containing up
to 5 mg of folic acid/ day were administered during pregnancy, there was no evidence of
toxicity or additional side-effects when compared to women receiving a placebo (14).
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1. Quality of the evidence The overall quality of evidence comparing intermittent iron supplementation to placebo
or no intervention was low for outcomes of anaemia, haemoglobin, iron deficiency and
ferritin (2).
The overall quality of evidence comparing intermittent iron supplementation to daily
supplementation was moderate for the outcome of anaemia; however, for the outcomes of
haemoglobin and ferritin, the quality of evidence was low, and for iron deficiency it was
very low (2).
2. Summary of the evidence The results from the systematic review (2) show (Appendix A) that intermittent
supplementation with iron (either alone or in combination with other nutrients) is
effective in reducing anaemia among menstruating women compared to no
supplementation or placebo (RR 0.73, 95% CI 0.56 to 0.95) (2). Evidence from 13
studies (2599 participants) shows that there is a significant increase in haemoglobin
concentration (MD 4.58 g/l, 95% CI 2.56 to 6.59) with supplementation (2). Additionally,
six studies (980 participants) showed that supplementation significantly increases ferritin
concentrations (MD 8.32 μg/l, 95% CI 4.97 to 11.66), compared to no intervention or
placebo (2). Furthermore, the evidence shows that the benefits are seen with intermittent
iron supplementation, either alone or in combination with folic acid or other
micronutrients (2). The greatest benefits of intermittent supplementation are observed in
settings of moderate to high prevalence of anaemia (2).
The evidence also shows that the effect on haemoglobin concentration is similar in
patients who receive intermittent supplementation versus patients who receive daily iron
supplementation (MD -0.15 g/l, 95% CI -2.20 to 1.91) (2). However, the mean difference
in ferritin concentration was lower with intermittent supplementation compared to daily
supplementation (MD -11.32 μg/l, 95% CI-22.61 to -0.02) and the risk of anaemia was
higher in women receiving intermittent supplementation as compared to women receiving
daily iron supplements (RR 1.26, 95% CI 1.04 to 1.51) (2).
The review found evidence that intermittent supplementation with iron (with or without
folic acid) in menstruating women is effective in decreasing risk of anaemia and
increasing hemoglobin and ferritin concentrations (2). The positive effect of the
intermittent supplement was seen in patients receiving iron once or twice a week (2).
Furthermore, the haematological response was seen with supplementation containing
more or less than 60 mg of elemental iron for a duration of more or less than 3 months
(2).
Although adherence has been claimed as one of the advantages of this intervention, its
reporting is still inadequate. Results of three studies (556 participants) comparing
Page 13 of 23
adherence to intermittent iron supplementation versus no supplementation or placebo
were not statistically significant (RR 0.99, 95% CI 0.96 to 1.01) (2). Four studies with
507 participants comparing intermittent supplementation to daily supplementation also
found no difference in adherence (RR 1.04, 95% CI 0.99 to 1.09) (2).
The most common side-effects of iron supplementation include nausea, constipation, dark
stools and metallic taste (2). As shown in Appendix C, the current evidence suggests
there is no significant difference is adverse side-effects between once weekly,
intermittent iron supplementation versus no intervention or placebo (RR 1.98, 95% CI
0.31 to 12.72) and between once weekly intermittent iron supplementation versus daily
iron supplementation (RR 0.36, 95% CI 0.10 to 1.31) (2).
IX. WHO guidelines on intermittent iron and folic acid
supplementation The WHO Department of Nutrition for Health and Development released an interim
statement in 2009 on weekly iron and folic acid supplementation (15), which was further
informed by a Cochrane systematic review. These updated guidelines on intermittent iron
and folic supplementation for menstruating women were published in 2011 (3). Even
though the overall quality of evidence for outcomes of iron supplementation, intermittent
or daily, with or without folic acid, ranges from low to moderate, the strength of the
recommendation is strong (3).
The guideline development group felt that the evidence suggests that once weekly,
intermittent supplementation with iron in menstruating women is effective in increasing
haemoglobin and ferritin levels and in reducing the prevalence of anaemia and this is one
of the few public health interventions widely supported by program experience (3).
Intermittent supplementation with iron and folic acid in women, delivered by variety of
channels ,has been a successful intervention in several countries (Cambodia, Egypt, Laos,
the Philippines and Viet Nam), reaching over a half a million women. In general, the
compliance has been high, with a decrease in the prevalence of anaemia between 9.3%
and 56.8% (9).
Furthermore, citing experimental evidence, the guidelines provide a strong
recommendation for using 2.8 mg folic acid alongside 60 mg elemental iron to reduce
risk of neural tube defects in a fetus should the woman or adolescent girl become
pregnant (2, 5). Therefore, WHO guidelines recommend the following schedule of iron
and folic acid supplementation as a public health intervention to reduce the risk of
anaemia in menstruating women and neural tube defects in newborn children for
menstruating women and adolescent girls living in settings where anaemia is 20% or
higher (5).
Page 14 of 23
Table 2 - Suggested scheme for intermittent iron and folic acid supplementation in menstruating women
Target Group All menstruating adolescent girls and adult women
Supplement
composition
Iron: 60 mg of elemental iron*
Folic acid: 2800 μg (2.8 mg)
Supplement form Tablets/capsules
Frequency One supplement per week
Duration and time
interval between periods
of supplementation
3 months of supplementation followed by 3 months of no
supplementation after which the provision of
supplements should restart.
If feasible, intermittent supplements could be given
throughout the school or calendar year
Settings
Populations where the prevalence of anaemia among non-
pregnant women of reproductive age is 20% or higher
*60 mg of elemental iron equals 300 mg of ferrous sulfate heptahydrate, 180 mg of ferrous
fumarate or 500 mg of ferrous gluconate.
Page 15 of 23
X. Summary and recommendations There is sufficient evidence to show that intermittent supplementation with iron and folic acid is
a feasible and effective public health policy to decrease the risk of anaemia in menstruating
women and adolescent girls. The addition of folic acid can help prevent neural tube defect-
affected pregnancies should a woman become pregnant.
The recommendations for changes to the EML Section 10.1 - Antianaemia Medicines, are as
follows:
1. Add 60 mg elemental iron in a ferrous form plus 2.8 mg folic acid tablet/capsule formulation
for the prevention of anaemia in menstruating women.
a. Dose
i. 60 mg of elemental iron equals 300 mg of ferrous sulfate heptahydrate, 180 mg of
ferrous fumarate or 500 mg of ferrous gluconate.
b. Frequency and duration of intermittent supplementation
i. Once weekly for menstruating women for three months followed by 3 months of
no supplementation, after which the provision of supplements should restart.
ii. If feasible, intermittent supplements could be given throughout the school or
calendar year.
Page 16 of 23
XI. References
1. Report of the 18th WHO Expert Committee: The Selection and Use of Essential Medicines.
Geneva: World Health Organization, 2011.
2. Fernandez-Gaxiola AC, De-Regil LM. Intermittent iron supplementation for reducing anaemia
and its associated impairments in menstruating women. Cochrane Database of systematic
Reviews. 2011(12):CD009218. Epub 2011/12/14.
3. Guideline: Intermittent iron and folic acid supplementation in menstruating women. Geneva,
Switzerland: World Health Organization, 2011.
4. Stoltzfus RJ, L Mullany L, Black RE. Iron deficiency anaemia. In: Global and regional
burden of diseases attributable to selected major risk factors. Ezzati, M., Lopez, A.D., Rodgers,
A., Murray, C.J.L (eds). Geneva; World Health Organization 2004. Available at
http://www.who.int/publications/cra/chapters/volume1/0163-0210.pdf
5. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin
and Mineral Nutrition Information System. Geneva, World Health Organization, 2011
(WHO/NMH/NHD/MNM/11.1) (http://www.who.int/vmnis/indicators/haemoglobin.pdf,
accessed 1 November 2012).
6. Serum ferritin concentrations for the assessment of iron status and iron deficiency in
populations. Vitamin and Mineral Nutrition Information System. Geneva, World Health
Organization, 2011 (WHO/NMH/NHD/MNM/11.2).
http://www.who.int/vmnis/indicators/serum_ferritin.pdf , accessed 1 December 2012).
7. WHO/CDC. Assessing the iron status of populations: report of a joint World Health
Organization/ Centers for Disease Control and Prevention technical consultation on the
assessment of iron status at the population level. Geneva, World Health Organization, 2005.
Available at http://whqlibdoc.who.int/publications/2004/9241593156_eng.pdf
Page 17 of 23
8. WHO/UNICEF/UNU. Iron deficiency anaemia: assessment, prevention and control, a guide
for programme managers. Geneva, World Health Organization, 2001. Available at
http://www.who.int/nutrition/publications/micronutrients/anaemia_iron_deficiency/WHO_NHD
_01.3/en/index.html
9. Weekly iron and folic acid supplementation programmes for women of reproductive age: an
analysis of best programme practices. Manila, World Health Organization Regional Office for
the Western Pacific, 2011
10. De-Regil LM, Fernández-Gaxiola AC, Dowswell T, Peña-Rosas JP. Effects and safety of
periconceptional folate supplementation for preventing birth defects. Cochrane Database of
Systematic Reviews 2010, Issue 10. Art. No.: CD007950.
DOI:10.1002/14651858.CD007950.pub2.
11. Norsworthy B, Skeaff CM, Adank C, Green TJ. Effects of once-a-week or daily folic acid
supplementation on red blood cell folate concentrations in women. European Journal of Clinical
Nutrition. 2004 Mar;58(3):548-54
12. Martínez de Villarreal LE, Arredondo P, Hernández R, Villarreal JZ. Weekly administration
of folic acid and epidemiology of neural tube defects. Maternal and Child Health Journal. 2006
Sep;10(5):397-401.
13. Martínez de Villarreal L, Pérez JZ, Vázquez PA, Herrera RH, Campos Mdel R, López RA,
Ramírez JL, Sánchez JM, Villarreal JJ, Garza MT, Limón A, López AG, Bárcenas M, García JR,
Domínguez AS, Nuñez RH, Ayala JL, Martínez JG, González MT, Alvarez CG, Castro RN.
Decline of neural tube defects cases after a folic acid campaign in Nuevo León, México.
Teratology. 2002 Nov;66(5):249-56.
14. Peña-Rosas JP, De-Regil LM, Dowswell T, Viteri FE. Daily oral iron supplementation
during pregnancy. Cochrane Database Systematic Reviews. 2012 Dec 12;12:CD004736. doi:
10.1002/14651858.CD004736.pub4.
15. Weekly iron–folic acid supplementation (WIFS) in women of reproductive age: its role in
promoting optimal maternal and child health. Position statement. Geneva, World Health
Organization, 2009
(http://www.who.int/nutrition/publications/micronutrients/weekly_iron_folicacid.pdf, accessed
10 December 2012).
Page 18 of 23
16. MSH. International Drug Price Indicator Guide. Management Sciences for Health, 2011.
17. UNICEF. Supply Catalogue. available at
https://supply.unicef.org/unicef_b2c/app/displayApp/%28layout=7.0-
12_1_66_67_115&carea=%24ROOT%29/.do?rf=y
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Page 19 of 23
Appendix A: Summary of Findings (GRADE) tables 1. Intermittent use of iron supplements versus placebo or no intervention
Page 20 of 23
2. Intermittent versus daily use of iron supplements
Page 21 of 23
Appendix B: Dosing and efficacy evidence 1. Comparison 1: Intermittent iron supplementation versus placebo or no intervention
Comparison 1: Intermittent iron supplementation versus placebo or no intervention
# Outcome No of Studies No of Participants Effect size (RR*)
1 Anaemia (for all) 10 2996 0.73 [0.56, 0.95]
2 Anaemia with 60 mg (or less) elemental iron
per week 5 1855
0.68 [0.43, 1.10]
3 Anaemia by intervention (iron alone) 2 292 0.45 [0.09, 2.13]
4 Anaemia by intervention (iron plus folic
acid) 7 1732
0.82 [0.64, 1.04]
RR = average relative risk
Comparison 1: Intermittent iron supplementation versus placebo or no intervention
# Outcome No of Studies No of Participants Effect size (MD*)
1 Haemoglobin (for all) 13 2599
4.58 g/l
[2.56, 6.59]
2 Haemoglobin with 60 mg (or less) elemental
iron per week 6 971
5.21 g/l
[2.06, 8.36]
3 Haemoglobin by intervention (iron alone) 4 606
6.13 g/l
[1.90, 10.36]
4 Haemoglobin by intervention (iron plus folic
acid) 8 1671
3.56 g/l
[1.11, 6.01]
MD = Mean Difference
Comparison 1: Intermittent iron supplementation versus placebo or no intervention
# Outcome No of Studies No of Participants Effect size (MD*)
1 Ferritin (for all) 6 980
8.32 μg/l
[4.97, 11.61]
2 Ferritin with 60 mg (or less) elemental iron
per week 3 269
12.37 μg/l
[7.06, 17.69]
3 Ferritin by intervention (iron alone) 2 204
7.80 μg/l
[1.38, 14.23]
4 Ferritin by intervention (iron plus folic
acid) 3 455
5.87 μg/l [3.23,
8.52]
MD = Mean Difference
Page 22 of 23
2. Comparison 2: Intermittent iron supplementation versus daily iron supplementation
Comparison 2: Intermittent iron supplementation versus daily iron supplementation
# Outcome No of Studies No of Participants Effect size (RR*)
1 Anaemia (for all) 6 1492 1.26 [1.04, 1.51]
2 Anaemia with 60 mg (or less) elemental iron
per week 4 614
1.23 [0.82, 1.85]
3 Anaemia by intervention (iron alone) 3 690 1.39 [0.97, 1.99]
4 Anaemia by intervention (iron plus folic
acid) 2 604
1.23 [0.98, 1.53]
RR = average relative risk
Comparison 2: Intermittent iron supplementation versus daily iron supplementation
# Outcome No of Studies No of Participants Effect size (MD*)
1 Haemoglobin (for all) 8 1676
-0.15 g/l
[-2.20, 1.91]
2 Haemoglobin with 60 mg (or less) elemental
iron per week 6 843
1.14 g/l
[-0.34, 2.62]
3 Haemoglobin by intervention (iron alone) 4 671
0.31 g/l
[-1.15, 1.78]
4 Haemoglobin by intervention (iron plus folic
acid) 3 807
-0.99 g/l
[-6.10, 4.13]
MD = Mean Difference
Comparison 2: Intermittent iron supplementation versus daily iron supplementation
# Outcome No of Studies No of Participants Effect size (MD*)
1 Ferritin (for all) 3 657
-11.32 μg/l
[-22.61, -0..02]
2 Ferritin with 60 mg (or less) elemental iron
per week
… … …
3 Ferritin by intervention (iron alone) … … …
4 Ferritin by intervention (iron plus folic
acid)
… … …
MD = Mean Difference
Page 23 of 23
Appendix C: Safety profile of iron supplementation 1. Intermittent iron supplementation versus placebo or no intervention
Intermittent iron supplementation versus placebo or no intervention
# Outcome No of Studies No of Participants Effect size (RR*)
1 All cause morbidity 1 119 1.12 [0.82, 1.52]
2 Any side effects 3 630 1.98 [0.31, 12.72]
3 Diarrhea 1 209 0.28 [0.05, 1.49]
RR = average relative risk
2. Intermittent iron supplementation versus daily iron supplementation
Intermittent iron supplementation versus daily iron supplementation
# Outcome No of Studies No of Participants Effect size (RR*)
1 Diarrhea 1 198 2.41 [0.12, 49.43]
2 Any side effects 4 823 0.36 [0.10, 1.31]
RR = average relative risk